Implication of Monoclonal Antibody for Covid-19

Journal of Institute of Science and Technology, 25(2), 133-139 (2020) ISSN: 2469-9062 (print), 2467-9240 (e) © IOST, Tribhuvan University Doi: https://doi.org/10.3126/jist.v25i2.33750 Review Article

IMPLICATION OF MONOCLONAL ANTIBODY FOR COVID-19 TREATMENT Reshma Tuladhar* Central Department of Microbiology, Tribhuvan University, Kathmandu, Nepal *Corresponding author: [email protected] (Received: September 10, 2020; Revised: November 25, 2020; Accepted: November 30, 2020)

ABSTRACT Coronavirus induced disease-19 (COVID-19) pandemic affecting entire world has continued to pose threat despite nearly a year of its onset. With more than 50 vaccine candidates targeting COVID-19 on trials and 15 at the final stage of testing, wide availability to the general public is still a long way to go. Thus alternative therapeutics is in the progress to minimize the effect of COVID-19. This systematic review evaluated the articles related to immunotherapy for COVID- 19. PubMed database was used to search for keywords; COVID-19, immunotherapy, and monoclonal antibody for relevant publications of the year 2020. The review was performed based on PRISMA protocol and the final 20 articles were included in the final review. These studies demonstrated that Tocilizumab, the monoclonal antibody that blocks IL- 6 receptors has improved outcome in COVID-19 infected patients. Keywords: Immunotherapy, Monoclonal antibody, PRISMA, SARS-CoV-2, Tocilizumab. immune response against SARS-CoV-2 infection INTRODUCTION contributing to the severity of the disease (Li et al., 2020). The pandemic of Corona Virus Induced Disease-2019 Containment of COVID-19 has also been challenged by (COVID-19) outbreak caused by Severe Acute an ambiguous pathogenesis mechanism. This has lead to Respiratory Syndrome Corona virus 2 (SARS-CoV-2) has an uncertainty in the therapeutics specifically targeting claimed over 1.7 million lives with more than 76 million SARS-CoV-2. The recently introduced vaccines approved infected globally (WHO, 2020). This highly contagious after the third phase of trial are yet to be assessed. disease spread by the respiratory droplets of infected Immunotherapy has been an efficient option considering person and has expanded across the world due to high its successful use against the closely related viruses transmission rate. Compared to the closely related beta SARS-CoV and MERS-CoV. Thus the purpose of this coronaviruses, the Middle East Respiratory Syndrome article is to review the use of monoclonal antibody, as an Coronavirus (MERS-CoV) and Severe Acute Respiratory immunotherapeutic against novel corona virus SARS- Syndrome Coronavirus (SARS-CoV), transmission rate in CoV-2 to ameliorate the condition of patient. SARS-CoV-2 is relatively high with large fraction contributed by asymptomatic carriers (Al-Tawfiq & METHODS Gautret, 2019; Wilder-Smith et al., 2005). The disease Search strategy induced by SARS-CoV-2 range from asymptomatic, noted without any signs and symptoms to symptomatic mild A systematic literature review was performed to phase involving upper airway and/or severe lethal state summarize information on monoclonal antibody infiltrating the lungs with progression to acute respiratory therapeutics for COVID-19 following the Preferred distress syndrome (ARDS) (Asadi et al., 2020; Shi et al., Reporting Items for Systematic Reviews and Meta- 2020). Analysis (PRISMA) guidelines. The main cause of death in COVID-19 infected patient is A literature search was conducted using PubMed database ARDS, which is associated with uncontrolled for keywords such as, COVID-19, immunotherapy, inflammatory response resulting from the release of pro- monoclonal antibody, and related words. The search inflammatory cytokines and chemokines- the cytokine included published articles for the year 2020. Title and storm (Li et al., 2020). Patients with COVID-19 have abstracts were reviewed to detect the related articles. increased plasma concentration of inflammatory Articles that have mentioned about immunotherapy for cytokines, such as Interleukins (IL), and over expression COVID-19 were selected. The articles with only abstract of tumor necrosis factor α (TNF α), granulocyte were excluded. Similarly articles that did not mention macrophagy-colony stimulating factors (GM-CSF), about the immunotherapeutic for the treatment of monocyte chemoattractant protein1, macrophage infection due to SARS-CoV-2 but only SARS, MERS, inflammatory protein 1 alpha, and interferon-γ-inducible other viruses and ailments were excluded. The full texts of protein 10 (Rothan et al., 2020). Cytokine release the relevant articles were read to decide on whether they syndrome has been suggested to hinder the adaptive could be included.

Implication of monoclonal antibody for COVID-19 treatment Data extraction and presentation articles and experiment protocols were not considered so 37 such articles were excluded in the initial search. Then Data from the articles were extracted after reading the from the remaining 127 articles, 59 were excluded after articles which were presented in the tables as summary. full text screen since full text could not be retrieved for This review addressed six domains: drug name, target site, some while others were not related to monoclonal route of administration, outcome of treatment, authors, antibody therapeutics. Finally 48 articles without data on and article type. SARS-CoV-2, but rather MERS, SARS, cancer and RESULTS arthritis were excluded. A total of 20 articles were included in the final review (Fig. 1). A total of 164 non-duplicate potentially eligible articles were retrieved from the database search. The review

Fig. 1. The article search flow chart From the extracted data, humanized monoclonal antibody 2020). Recovery in the patient with marked decreased C- used for SARS-CoV-2 incorporated were Tocilizumab, reactive protein (CRP) level in blood and improvement in Sarilumab, Itolizumab, Siltuximab, Infliximab and inflammatory markers with reduced fever were the Lenzilumab. The monoclonal antibodies that target commonly observed features in the patient treated with interleukin-6 receptor included in Table 1 are Tocilizumab these interleukin-6 receptor blockers. The recovery time and Sarilumab. They are administered intravenously, however varied with the authors. The improvement period although some have been introduced subcutaneously into ranged from 5 days to two weeks as mentioned in most of the patient (Hassoun et al., 2020; Montesarchio et al., the literature. Substantial research articles available on

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R. Tuladhar Tocilizumab treatment demonstrated faster recovery compared to Sarilumab.

Table 1. Overview of interleukin 6 receptor target monoclonal antibody for COVID-19 treatment

Target Route of Drug name site administration Outcome of treatment Author Article type CRP decreased significantly, IL6 elevated at beginning then decreased afterwards Luo et al. (2020) Research CRP decreased within 2-6 Di Giambenedetto et days. IL6 was not detected al. (2020) Research Improvement in inflammatory markers within 7 days, improvement in clinical Hassoun et al. Subcutaneous syndrome (2020) Research CRP decreased Tocilizumab significantly, fever normal Intravenous after 1 day Xu et al. (2020) Research CRP decreased, fever reduced, peripheral Intravenous lymphocyte increased Zhao (2020) Research Interleukin CRP decreased, fever 6 receptor reduced, radiological Intravenous improvement Alattar et al. (2020) Temp returned to normal quickly after treatment, 20 out of 21 patients discharged after 2 weeks, no adverse effect, Fu et al. (2020) Commentary 89.7 % patients improved Gremese et al. Intravenous in 19 days, (2020) Research CRP level decreased, mostly below upper normal Montesarchio Subcutaneous range within 5 days et al. (2020) Report Sarilumab CRP normalized in 6 days compared to 12 days in Della-Torre et al. Intravenous control group (2020) Report Caballero Bermejo Partial improvement et al. (2020) Trial

The anti-CD6 monoclonal antibody, Itolizumab, improvement in cytokine level in serum with decreased decreased the level of IL-6 in the serum within 48 hours IL6 and IL8 when Infliximab, the TNF alpha target was of intravenous administration (Table 2). Similarly, administered intravenous. Lenzilumab, the granulocyte- Siltuximab, which directly binds Interleukin-6 delayed monocyte colony stimulating factor (GM-CSF) target, did normalization of IL-6 compared to Tocilizumab when not improve the symptoms within 24 hours of intravenous administered subcutaneous. Reduction of CRP in 76 % administration (Melody et al., 2020) but improvement in patient with 33 % clinical improvement was reported in a CRP and inflammatory cytokines was reported in other research (Table 2). Similarly, a case study reported an study (Temesgen et al., 2020). 135

Implication of monoclonal antibody for COVID-19 treatment

Table 2. Overview of monoclonal antibody with different target site for COVID-19 treatment

Route of Article Drug name Target site administration Outcome of treatment Author type Anticipated in treating cytokine Loganathan et al. Intravenous storm, anti-inflammatory (2020) Trial Circulating IL6 decreased within CD6 Itolizumab Intravenous 48 hrs. Diaz et al. (2020) Research receptor Intravenous Serum IL6 decreased after 48 hrs Atal et al. (2020) Research IL6 decreased after 1 dose in 48 Saavedra et al. Intravenous hours (2020) Research Delayed normalization of IL6 Palanques Pastor Subcutaneous compared to Tocilizumab et al. Report Siltuximab Interleukin-6 CRP reduced in 76% patient, Intravenous Clinical improvement in 33% Gritti et al. (2020) Research Cytokine improved, Infliximab normalization of TNF alpha, Dolinger et al. TNF-alpha Intravenous decreased IL6 and IL8 (2020) Case study Symptom did not improve but 24 hours after administration of Tocilizumab improvement in Melody et al. Granulocyte- Intravenous CRP and Interleukins (2020) Case study monocyte Clinical improvement in treated Lenzilumab colony patient in 5 days compared to 12 stimulating days in non-treated control; factor reduced inflammatory myeloid cells in 2 days, Improvement in CRP and inflammatory Temesgen et al. Intravenous cytokines (2020)

DISCUSSION Tocilizumab and Sarilumab, target and antagonize both membrane-bound and soluble IL-6 receptor. The food and Attachment and entry into the host cell is the primary drug administration (FDA) approved Tocilizumab has strategy exploited by virus and other pathogens in the been reported with the promising preliminary clinical process of infection. Therapeutics to block the attachment results from clinical trials and devoid adverse reaction (Fu and entry are promising approach in thwarting the et al., 2020). Improvement in the symptoms of patient pathogenesis mechanism elicited by the virus. Monoclonal followed by switching to the use of Tocilizumab was antibodies that recognize different epitopes on the viral evident when the previously used Lenzilumab did not surface have been effective immunotherapy owing to their show any progress (Melody et al., 2020). Gradual specificity, purity and safety. decrease in IL-6 level in patient treated with Tocilizumab A characteristic feature in COVID-19 being cytokine due to inhibition of inflammatory activity and storms induced by virus, immunotherapy targeting the improvement in clinical outcome has been reported cytokines can help ameliorate the condition. IL-6 is (Hassoun et al., 2020; Luo et al., 2020). Sarilumab was considered a key cytokine in COVID-19 due to its used in Italy to treat patients with severe SARS-CoV-2 elevation correlated with the severity induced by cytokine pneumonia (Della-Torre et al., 2020) and in China as an storm (Crisafulli et al., 2020; Damas et al., 1992). An alternative anti-IL-6 receptor during the shortage of approach for the treatment of rheumatoid arthritis by Tocilizmab (Gremese et al., 2020). Available in both blocking IL-6 receptor has been a strategy adopted to intravenous and subcutaneous formulation, it was calm the inflammatory storm with the use of Tocilizumab effective with good clinical outcome and do not present (Alfonso-Cristancho et al., 2017; Fu et al., 2020). adverse effect (Della-Torre et al., 2020; Gremese et al., 2020).

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R. Tuladhar A CD6 receptor target, Itolizumab reduce the activation, (MERS-CoV) infection: extent and implications for proliferation, and differentiation of T cells into pathogenic infection control: a systematic review. Travel effector T cells leading to a decrease in production of Medicine and Infectious Disease, 27, 27-32. proinflammatory cytokine (Nair et al., 2010). This drug Asadi, S., Bouvier, N., Wexler, A., & Ristenpart, W. has been approved in India for psoriasis treatment and is (2020). The coronavirus pandemic and aerosols: used for COVID-19 patients with moderate to severe Does COVID 19 transmit via expiratory particles? ARDS (Longanathan et al., 2020). Unike Tocilizumab Aerosol Science and Technoogy, 54, 635-638. and Sarilumab, the IL-6 target drug Siltuximab have affinity with IL-6. Though the efficacy of Siltuximab has Atal, S., Fatima, Z., & Balakrishnan, S. (2020). Approval been reported to be identical to Tocilizumab, it has of Itolizumab for COVID-19: A Premature Decision produced a delayed normalization of IL-6 levels compared or Need of The Hour? BioDrugs, 34(6), 705-711. to the latter (Palanques-Pastor et al., 2020). Caballero Bermejo, A. F., Ruiz-Antoran, B., Fernandez In a case study, involving a patient with Crohn’s disease Cruz, A., Diago Sempere, E., Callejas Diaz, A., who was suspected with COVID-19, Infliximab was Munez Rubio, E., Avendano-Sola, C., Ramos administered to co-manage both entities (Dolinger et al., Martinez, A., & Sancho Lopez, A. (2020). Sarilumab 2020). Since the inflammatory disease overlapped, the versus standard of care for the early treatment of real picture of cytokine storm induced by SARS-CoV-2 COVID-19 pneumonia in hospitalized patients: was not confirmed in that study. Thus they recommended SARTRE: a structured summary of a study protocol further investigation for implication in COVID-19. for a randomised controlled trial. Trials, 21(1), 794. Improvement in inflammatory markers with patient https://doi.org/10.1186/s13063-020-04633-3 treated with Lenzilumab, the GM-CSF target, has been reported (Temesgen et al., 2020). However, randomized Crisafulli, S., Isgro, V., La Corte, L., Atzeni, F., & Trifiro, G. (2020). Potential Role of Anti-interleukin (IL)-6 control clinical trial needs to validate the outcome of the Drugs in the Treatment of COVID-19: Rationale, treatment. A case study has asserted the superiority of Clinical Evidence and Risks. BioDrugs, 34(4), 415- Tocilizumab over Lenzilumab in the management of 422. cytokine mediated syndrome (Melody et al., 2020). Damas, P., Ledoux, D., Nys, M., Vrindts, Y., De Groote, CONCLUSION D., Franchimont, P., & Lamy, M. (1992). Cytokine Considering all the evidences from the selected articles serum level during severe sepsis in human IL-6 as a reviewed, Tocilizumab continues to be the most effective marker of severity. Annals of Surgery, 215(4), 356- among the currently introduced monoclonal antibody 362. therapeutics for the improvement of clinical outcomes in COVID-19 infected patients. Della-Torre, E., Campochiaro, C., Cavalli, G., De Luca, G., Napolitano, A., La Marca, S., Boffini, N., Da ACKNOWLEDGEMENTS Prat, V., Di Terlizzi, G., Lanzillotta, M., Rovere The author would like to thank Institute of Science and Querini, P., Ruggeri, A., Landoni, G., Tresoldi, M., Technology, Tribhuvan University. Ciceri, F., Zangrillo, A., De Cobelli, F., & Dagna, L. (2020). Interleukin-6 blockade with sarilumab in REFERENCES severe COVID-19 pneumonia with systemic hyperinflammation: an open-label cohort study. Alattar, R., Ibrahim, T. B. H., Shaar, S. H., Abdalla, S., Shukri, K., Daghfal, J. N., Khatib, M. Y., Annals of Rheumatic Disease, 79(10), 1277-1285. Aboukamar, M., Abukhattab, M., Alsoub, H. A., Di Giambenedetto, S., Ciccullo, A., Borghetti, A., Almaslamani, M. A., & Omrani, A. S. (2020). Gambassi, G., Landi, F., Visconti, E., Verme, Tocilizumab for the treatment of severe coronavirus L.Z.D., Bernabei, R., Tamburrini, E., Cauda, R., & disease 2019. Journal of Medical Virology, 92(10), Gasbarrini, A. (2020). Off-label use of tocilizumab 2042-2049. in patients with SARS-CoV-2 infection. Journal of Alfonso-Cristancho, R., Armstrong, N., Arjunji, R., Medical Virology, 92(10), 1787-1788. Riemsma, R., Worthy, G., Ganguly, R., & Kleijnen, Diaz, Y., Ramos-Suzarte, M., Martin, Y., Calderon, N. A., J. (2017). Comparative effectiveness of biologics for Santiago, W., Vinet, O., La, O.Y., Oyarzabal, J.P.A., the management of rheumatoid arthritis: systematic Perez, Y., Lorenzo, G., Cepeda, M., Saavedra, D., review and network meta-analysis. Clinical Mazorra, Z., Estevez, D., Lorenzo-Luaces, P., Rheumatology, 36(1), 25-34. Valenzuela, C., Caballero, A., Leon, K., Crombet, Al-Tawfiq, J., & Gautret, P. (2019). Asymptomatic T., & Hidalgo, C. J. (2020). Use of a humanized Middle East Respiratory Syndrome Coronavirus anti-CD6 monoclonal antibody (Itolizumab) in

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